In 1989, a main causative virus of non-A non-B posttransfusion hepatitis was found and named hepatitis C virus (HCV). Since then, several types of hepatitis viruses have been found besides type A, type B and type C, wherein hepatitis caused by HCV is called hepatitis C.
The patients infected with HCV are considered to involve several percent of the world population, and the infection with HCV characteristically becomes chronic.
HCV is an envelope RNA virus, wherein the genome is a single strand plus-strand RNA, and belongs to the genus Hepacivirus of Flavivirus (from The International Committee on Taxonomy of Viruses, International Union of Microbiological Societies). Of the same hepatitis viruses, for example, hepatitis B virus (HBV), which is a DNA virus, is eliminated by the immune system and the infection with this virus ends in an acute infection except for neonates and infants having yet immature immunological competence. In contrast, HCV somehow avoids the immune system of the host due to an unknown mechanism. Once infected with this virus, even an adult having a mature immune system frequently develops persistent infection. When chronic hepatitis is associated with the persistent infection with HCV, it advances to cirrhosis or hepatic cancer in a high rate. Enucleation of tumor by operation does not help much, because the patient often develops recurrent hepatic cancer due to the sequela inflammation in non-cancerous parts. In addition, there is a report on the involvement of HCV infection in dermatosis such as chronic urticaria, lichen planus, cryoglobulinemic purpura and the like (The Japanese Journal of Dermatology, Vol. 111, No. 7, pages 1075-1081, 2001).
Thus, an effective therapeutic method of hepatitis C is desired. Apart from the symptomatic therapy to suppress inflammation with an anti-inflammatory agent, the development of a therapeutic agent that reduces HCV to a low level free from inflammation and that eradicates HCV has been strongly demanded.
At present, a treatment with interferon is the only effective method known for the eradication of HCV. However, interferon can eradicate the virus only in about one-third of the patient population. For the rest of the patients, it has no effect or provides only a temporary effect. In recent years, polyethylene glycolated interferon has been put to practical use, and enhanced effects and reduced side effects have been achieved. However, complete response rate still remains at a low level, and therefore, an anti-HCV drug to be used in the place of or concurrently with interferon is awaited in great expectation.
In recent years, Ribavirin (1-β-D-ribofuranosyl-1H-1,2,4-triazole-3-carboxamide) has become commercially available as a therapeutic agent for hepatitis C, which is to be used concurrently with interferon. It enhances the efficacy of interferon but only to a low efficacy rate, and a different novel therapeutic agent for hepatitis C is desired.
Also, an attempt has been made to potentiate the immunocompetence of the patient with an interferon agonist, an interleukin-12 agonist and the like, thereby to eradicate the virus, but an effective pharmaceutical agent has not been found yet.
In addition, the inhibition of HCV growth, wherein HCV-specific protein is targeted, has been drawing attention these days.
The gene of HCV encodes a protein such as serine protease, RNA helicase, RNA-dependent RNA polymerase and the like. These proteins function as a specific protein essential for the growth of HCV.
One of the specific proteins, RNA-dependent RNA polymerase (hereinafter to be also briefly referred to as an HCV polymerase), is an enzyme essential for the growth of the virus. The gene replication of HCV having a plus-strand RNA gene is considered to involve synthesis of a complementary minus-strand RNA by the use of the plus-strand RNA as a template and using the obtained minus-strand RNA as a template, amplifying the plus-strand RNA. The portion called NS5B of a protein precursor, that HCV codes for, has been found to show an RNA-dependent RNA polymerase activity (EMBO J., Vol, 15, pages 12-22, 1996), and is considered to play a central role in the HCV gene replication.
Therefore, an HCV polymerase inhibitor can be a target in the development of an anti-HCV drug, and the development thereof is eagerly awaited. However, an effective HCV polymerase inhibitor has not been developed yet, like in other attempts to develop an anti-HCV drug based on other action mechanisms. As the situation stands, no pharmaceutical agent can treat hepatitis C satisfactorily.
The following describes known compounds comparatively similar to the present invention.
WO03/099824 discloses the following compound a etc. as anti-HCV agents, and teaches that this compound shows an HCV polymerase inhibitory action (WO03/099824, Example 4 (page 32, line 10-page 35), Table 1 (page 20)).

However, the compound of the present invention is not disclosed therein and no description suggestive thereof is found in the specification.
On the other hand, as known tetracyclic fused heterocyclic compounds, whose pharmaceutical use is known, the following can be mentioned.
EP226508 discloses that the following compound b etc. show an anticancerous action (EP226508, Example 2 (page 4, last line—page 6, line 2), formula VII of claim 5 (page 31)).

Other reference describes following compound c etc. and synthetic methods of compounds usable as central nervous system agents (Bollettino Chimico Farmaceutico, Vol. 120, No. 2, pages 102-107, 1981).

However, none of these references discloses the compound of the present invention, not to mention disclosure of use of the compounds of these references as antiviral agents or description suggestive thereof.
As the compounds comparatively similar to the compound of the present invention, relating to use other than a pharmaceutical agent, the following can be mentioned.
JP-A-4-329547 discloses the following compound d known as an electronic photographic-sensitized material (JP-A-4-329547, formula 52 (page 7, lower right column)).

A different reference discloses the following compound e etc., wherein its synthetic method is described (J. Org. Chem., Vol. 66, No. 2, pages 412-420, 2001, Table 3 No. 19 (page 415)).

A yet different reference discloses the following compound f etc., wherein its synthetic method is described (Organic Letters, Vol. 4, No. 8, pages 1355-1358, 2002, Table 1 No. 17 (page 1357), Scheme 4 (page 1356)).

Another different reference discloses the following compound g etc., wherein its synthetic method is described (J. Org. Chem., Vol. 31, No. 6, pages 2009-2011, 1966, Scheme 1 (page 2010)).

However, none of these references discloses the compound of the present invention, not to mention disclosure of use of the compounds of these references as an antiviral agents or description suggestive thereof.
As a therapeutic agent for hepatitis C having an indole skeleton, WO03/010140 is known (WO03/010140, Example Nos. 1 (page 41), 10 (page 51), 14 (page 57), 18 (page 60), 20 (page 63), 22 (page 64), compound No. 149 (page 79)).
In this publication, as an anti-HCV agent having a polymerase inhibitory activity, the following indole compounds A, B, C, D etc. are described.
wherein Ex. means Example No. in the publication.
In this publication, as compounds having other skeleton, the following compounds E, F, G etc. are described.

In WO03/010141, as a synthetic intermediate for an anti-HCV agent having a polymerase inhibitory activity, the above-mentioned compounds etc. are described (WO03/010141, page 92, page 101, page 108, page 112, page 115, page 116).
Furthermore, JP-A-2001-247550 (WO01/47883, EP1162196A1, US2003/0050320) and WO03/000254 (US2003/0050320) describe, as an anti-HCV agent having a polymerase inhibitory activity, the following indole compound H etc., benzimidazole compound I etc. (JP-A-2001-247550, Example compound Nos. 502 (page 206), 701 (page 417), 1198 (page 315); WO03/000254, Example compound Nos. 502 (page 206), 701 (page 417), 1198 (page 315), 371 (page 468), 405 (page 479), 407 (page 480), 423, 424 (page 485)).

This publication also describes the following compound J etc. as compounds having other skeletons.

The above-mentioned WO03/000254 further describes the following benzimidazole compounds K, L, M, N, O etc.

In addition, WO02/04425 describes the following benzimidazole compound P etc. as anti-HCV agents having a polymerase inhibitory activity (WO02/04425, entry No. 7005 (page 228), Example Nos. 28 (page 84), 148 (page 163)).

In this publication, the following compounds Q, R etc. are described as compounds having other skeletons.

WO03/026587 also discloses the following compounds S, T etc. as anti-HCV agents having a polymerase inhibitory activity (WO03/026587, Example Nos. 12 (page 56), 65 (page 65)).

As therapeutic agents for hepatitis C having a benzimidazole skeleton, the compounds described in WO97/36866, JP-T-2000-511899 (EP906097) and WO99/51619 are also known.
WO03/007945 also describes benzimidazole compound etc. as synthetic intermediates for anti-HCV agents having a polymerase inhibitory activity.
Furthermore, WO99/09007 and U.S. Pat. No. 5,932,743 describe the following indole compound U etc. as chemical library compounds that can be used for screening of pharmaceutical products (see WO99/09007, Example 12 (page 25); U.S. Pat. No. 5,932,743).
